Background

No consensus exists on how to reduce oral corticosteroids after the initiation of
biologics in severe asthma. The PONENTE trial evaluated the effectiveness and safety
of a rapid, individualised steroid-reduction algorithm, including adrenal insufficiency
monitoring, after benralizumab initiation.

Methods

This multicentre, open-label, single-arm study was done at 138 clinical asthma treatment
centres across 17 countries. We enrolled adult patients (age ≥18 years) with severe,
eosinophilic asthma (blood eosinophil count ≥150 cells per μL at enrolment or ≥300
cells per μL in the previous year) requiring maintenance oral corticosteroids for
at least 3 months preceding enrolment. Patients received benralizumab 30 mg (subcutaneous
injection) every 4 weeks for three doses, then every 8 weeks thereafter. The oral
corticosteroid reduction phase began at week 4 with daily oral corticosteroid dosages
reduced by 1–5 mg every 1–4 weeks depending on the starting dosage, asthma control,
and adrenal function status. Adrenal function was assessed with an early morning serum
cortisol measurement, followed by adrenocorticotropic hormone stimulation when required,
once patients achieved a daily oral corticosteroid dosage of 5 mg/day for 4 weeks.
Repeat cortisol measurements were taken for patients with evidence of adrenal insufficiency
at first testing. Asthma control was assessed with the Asthma Control Questionnaire-6
(ACQ-6) weekly throughout the induction and oral corticosteroid reduction phases.
The primary endpoints were the percentage of patients eliminating daily oral corticosteroids,
sustained for at least 4 weeks, and the percentage achieving elimination or a daily
prednisone or prednisolone dosage of 5 mg or less, for at least 4 weeks, if the reason
for no further reduction was adrenal insufficiency. Safety and efficacy analyses included
all patients who received at least one dose of benralizumab and were descriptive.
We present results after the oral corticosteroid reduction phase; a maintenance phase
is ongoing. The trial is registered with ClinicalTrials.gov, NCT03557307.

Findings

Between April 1, 2018, and Sept 5, 2020, of 705 patients assessed for eligibility,
598 were recruited and all received at least one dose of benralizumab. Overall, 376
(62·88%, 95% CI 58·86–66·76) of 598 patients eliminated oral corticosteroids and 490
(81·94%, 78·62–84·94) of 598 eliminated use or achieved a dosage of 5 mg or less if
the reason for stopping the reduction was adrenal insufficiency. Subgroup analysis
showed that dosage reductions were achieved irrespective of baseline eosinophil count,
baseline oral corticosteroid dosage, or oral corticosteroid treatment duration. Adrenal
insufficiency was detected in 321 (60%) of 533 patients at first assessment and in
205 (38%) of 533 patients 2–3 months later. The safety profile was consistent with
previous experience. Most patients (448 [75%] of 598) had no asthma exacerbations
during the oral corticosteroid reduction phase with an annualised exacerbation rate
of 0·63. Of 598 patients, 38 (6%) experienced a total of 46 exacerbations resulting
in emergency department or urgent care visits or hospitalisations.

Interpretation

Despite a high prevalence of adrenal insufficiency, most patients with eosinophilic
asthma treated with benralizumab achieved elimination of oral corticosteroids or maximal
possible reduction using a personalised dosage-reduction algorithm.

Funding

AstraZeneca.

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